Pyridazinone derivatives

ABSTRACT

Pyridazinone derivatives represented by the formula (I) and antiplatelet agents containing them: ##STR1##  wherein R is a hydrogen atom or a C 1  -C 4  alkyl group, X is a hydrogen atom, a chlorine atom or a bromine atom, Ar is a pyridyl group or a phenyl group substituted with OR 1  (wherein R 1  is a hydrogen atom or a C 1  -C 4  alkyl group) and A {wherein A is a hydrogen atom, a halogen atom, a C 1  -C 4  alkyl group or OR 2  (wherein R 2  is a hydrogen atom or a C 1  -C 4  alkyl group)}, Y is C 1  -C 8  alkylene wherein one carbon atom on the straight chain is substituted with one OR 1  group (wherein R 1  is the same as defined above), and Z 1  and Z 2  are independently a hydrogen atom, a halogen atom, a C 1  -C 4  alkyl group or a OR 1  group (wherein R 1  is the same as defined above)!. These compounds have strong antiplatelet effects, are excellently safe, and can be used as active ingredients of prophylactic and therapeutic drugs for various thrombotic diseases.

This is a Division of application Ser. No. 08/676,227 filed on Jul. 23,1996, which was filed as International Application No. PCT/JP95/00069,filed on Jan. 24, 1995.

TECHNICAL FIELD

The present invention relates to novel 3(2H)-pyridazinone derivativesand their salts having an antiplatelet action and pharmaceuticalcompositions containing them as active ingredients.

This application is a 371 of PCT/JP95/00069, filed Jan. 24, 1995.

BACKGROUND TECHNIQUE

It is known that platelet aggregation plays an important role inthrombus formation, in connection with a disease state. Main thromboticdiseases caused by thrombus formation include cerebral thrombosis,pulmonary thrombosis, myocardial infarction, angina pectoris, occlusionof peripheral arteries and the like, and all of these diseases requiredevelopment of useful drugs. As a prophylactic or therapeutic drug, anantiplatelet agent having an inhibitory action on platelet aggregationdraws public attention. Heretofore, the effect of aspirin has beenwidely studied, and more recently ticlopidine and cilostazol have beenclinically developed. However, they are not active enough or do not actselectively enough. Therefore, a more strongly effective drug isdemanded.

In addition to the above-mentioned various thrombotic diseases, variousdiseases are enumerated as related to platelets. Examples of thesediseases include nephritis, cancer cell metastasis and the like, andrecently various studies have been conducted with regard to prophylacticor therapeutic effects mainly on these diseases of an antiplatelet agenthaving an action of controlling the function of the platelet ("Journalof Royal College of Physicians", Vol. 7, No. 1, pp. 5-18, 1972; "JapanClinics (Nihon Rinsho)", Vol. 4, No. 6, pp. 130-136, 1988; AnticancerResearch, Vol 6, pp. 543-548, 1986).

Now, the relationship of 3(2H)-pyridazinone derivatives of the generalformula (I) and their salts according to the present invention withcompounds disclosed in published references will be described.

(a) German Laid Open Patent Application No. 1,670,169 (hereinafterreferred to as reference (a)) discloses 3(2H)-pyridazinone derivativeshaving a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic oraromatic group at the 2-position, a chlorine or bromine atom at the4-position, an amino group inclusive of an aralkylamino group at the5-position, and a chlorine or bromine atom or a hydroxy or C₁ -C₄ alkoxygroup at the 6-position.

This reference (a) discloses a process for synthesis of the3(2H)-pyridazinone derivatives, their application to agriculturalchemicals, their application as intermediates for medicines, dyestuffsor various other chemicals, and, however, neither mentions theirpharmacological activities nor gives any specific examples of suchcompounds. Further, such compounds are not specifically described.

(b) Japanese Unexamined Patent Publication No. 183675/1983 (hereinafterreferred to as reference (b)) discloses 3(2H)-pyridazinone derivativeshaving a lower alkyl group at the 2-position, a hydrogen atom at the4-position, a substituted or unsubstituted anilino group at the5-position and a hydroxyl group or a lower alkoxy group at the6-position. This reference (b) discloses that the 3(2H)-pyridazinonederivatives have an analgesic action, an anti-inflammatory action, ananti-allergic action and an anti-rheumatic action, but there is nospecific disclosure concerning their pharmacological activities.

(c) Japanese Unexamined Patent Publication No. 301870/1988, EuropeanLaid Open Patent Publication No. 275997 and U.S. Pat. No. 4,978,665(hereinafter referred to collectively as reference (c)) disclose6-substituted alkoxy-5-substituted benzylamino-3(2H)-pyridazinonederivatives, which are relatively similar to the compounds of thepresent invention and their use as an anti-SRS-A agent.

(d) International Patent Application WO-91/16314, European Laid OpenPatent Publication No. 482208 and U.S. Pat. No. 5,202,323 (hereinafterreferred to collectively as reference (d)) disclose 6-substitutedalkoxy-5-substituted arylamino-3(2H)-pyridazinone derivatives, which arerelatively similar to the compounds of the present invention, and theiruse as a platelet aggregation inhibitor, a cardiotonic, a vasodilatorand an anti-SRS-A agent.

The present invention relates to novel 3(2H)-pyridazinone compounds andtheir derivatives useful as an antiplatelet agent as an activeingredient of a prophylactic or therapeutic drug for thrombosis andother diseases attributable to pathological activation of the platelet.

DISCLOSURE OF THE INVENTION

As the result of the extensive study, the present inventors havediscovered that the 3(2H)-pyridazinone derivatives and their salts ofthe present invention, which are different from any compounds disclosedin the above references, are very selective and quite usefulantiplatelet agents which show an intense and broad spectrum ininhibition of platelet aggregation, hardly act on the heart or the bloodvessels and do not produce significant side effects such as headaches,depression, a drop in the blood pressure and palpitations, and that theycan be active ingredients of prophylactic or therapeutic drugs for theabove-mentioned various thrombotic diseases. On the basis of thisdiscovery, the present invention has been accomplished.

That is, the present invention relates to a 3(2H)-pyridazinonederivative represented by the general formula (I) and its salt, and apharmaceutical composition containing it as an active ingredient:##STR2## wherein R is a hydrogen atom or a C₁ -C₄ alkyl group,

X is a hydrogen atom, a chlorine atom or a bromine atom,

Ar is a pyridyl group or a phenyl group substituted with OR¹ (wherein R¹is a hydrogen atom or a C₁ -C₄ alkyl group) and A {wherein A is ahydrogen atom, a halogen atom, a C₁ -C₄ alkyl group or OR² (wherein R²is a hydrogen atom or a C₁ -C₄ alkyl group)},

Y is C₁ -C₈ alkylene wherein one carbon atom on the straight chain issubstituted with one OR¹ group (wherein R¹ is the same as definedabove), and

Z¹ and Z² are independently a hydrogen atom, a halogen atom, a C₁ -C₄alkyl group or a OR¹ group (wherein R¹ is the same as defined above)!.

Hereinafter, R, R¹, R², X, Y, Z¹, Z² and Ar in the above general formula(I) representing the compound of the present invention are explained.

R, R¹ and R² are respectively a hydrogen atom or a linear or branched C₁-C₄ alkyl group. Examples of them include a hydrogen group, a methylgroup, an ethyl group, a n-propyl group, an i-propyl group, a n-butylgroup, an i-butyl group, a sec-butyl group and a t-butyl group.

As examples of X, a hydrogen atom, a chlorine atom and a bromine atommay be mentioned.

Y is C₁ -C₈ alkylene wherein one carbon on the straight chain issubstituted with one OR¹ group (wherein R¹ is the same as definedabove). Examples of Y include hydroxymethylene, methoxymethylene,ethoxymethylene, propoxymethylene, butoxymethylene, 1-hydroxyethylene,2-hydroxyethylene, 1-methoxyethylene, 2-methoxyethylene,1-ethoxyethylene, 2-ethoxyethylene, 1-propoxyethylene,2-propoxyethylene, 1-butoxyethylene, 2-butoxyethylene,1-hydroxypropylene, 2-hydroxypropylene, 3-hydroxypropylene,1-methoxypropylene, 2-methoxypropylene, 3-methoxypropylene,1-ethoxypropylene, 2-ethoxypropylene, 3-ethoxypropylene,1-propoxypropylene, 2-propoxypropylene, 3-propoxypropylene,1-butoxypropylene, 2-butoxypropylene, 3-butoxypropylene,1-hydroxybutylene, 2-hydroxybutylene, 3-hydroxybutylene,4-hydroxybutylene, 1-methoxybutylene, 2-methoxybutylene,3-methoxybutylene, 4-methoxybutylene, 1-ethoxybutylene,2-ethoxybutylene, 3-ethoxybutylene, 4-ethoxybutylene, 1-propoxybutylene,2-propoxybutylene, 3-propoxybutylene, 4-propoxybutylene,1-butoxybutylene, 2-butoxybutylene, 3-butoxybutylene, 4-butoxybutylene,5-hydroxypentylene, 6-hydroxyhexylene, 7-hydrpxyheptylene,8-hydroxyoctylene, 1-hydroxy-1-methylmethylene,1-hydroxy-2-methylethylene, 2-ethyl-1-hydroxyethylene,1-hydroxy-2-propylethylene, 2-butyl-1-hydroxyethylene,1-hydroxy-2-pentylethylene, 2-hexyl-1-hydroxyethylene,2-hydroxy-1-methylethylene, 1-ethyl-2-hydroxyethylene,2-hydroxy-1-propylethylene, 1-butyl-2-hydroxyethylene,2-hydroxy-1-pentylethylene, 1-hexyl-2-hydroxyethylene,1-hydroxy-2-methylpropylene, 2-ethyl-1-hydroxypropylene,1-hydroxy-2-propylpropylene, 2-butyl-1-hydroxypropylene,1-hydroxy-3-methylpropylene, 3-ethyl-1-hydroxypropylene,1-hydroxy-3-propylpropylene, 3-butyl-1-hydroxypropylene,1-hydroxy-2-methylbutylene, 2-ethyl-1-hydroxybutylene,1-hydroxy-2-propylbutylene, 2-butyl-1-hydroxybutylene,1-hydroxy-3-methylbutylene, 3-ethyl-1-hydroxybutylene,1-hydroxy-3-propylbutylene, 3-butyl-1-hydroxybutylene,2,2-dimethyl-1-hydroxyethylene, 2,2-diethyl-1-hydroxyethylene,2,2-diisopropyl-1-hydroxyethylene, 1,1-dimethyl-2-hydroxyethylene,1,1-diethyl-2-hydroxyethylene, 1,1-diisopropyl-2-hydroxyethylene,2,2-dimethyl-1-hydroxypropylene, 2,2-diethyl-1-hydroxypropylene,1,1-dimethyl-2-hydroxypropylene, 1,1-diethyl-2-hydroxypropylene,3,3-dimethyl-1-hydroxypropylene, 3,3-diethyl-1-hydroxypropylene,3,3-dimethyl-2-hydroxypropylene, 3,3-diethyl-2-hydroxypropylene,1,1-dimethyl-3-hydroxypropylene, 1,1-diethyl-3-hydroxypropylene,2,2-dimethyl-3-hydroxypropylene, 2,2-diethyl-3-hydroxypropylene,2,2-dimethyl-1-hydroxybutylene, 2,2-diethyl-1-hydroxybutylene,1,1-dimethyl-2-hydroxybutylene, 1,1-diethyl-2-hydroxybutylene,3,3-dimethyl-1-hydroxybutylene, 3,3-diethyl-1-hydroxybutylene,3,3-dimethyl-2-hydroxybutylene, 3,3-diethyl-2-hydroxybutylene,1,1-dimethyl-3-hydroxybutylene, 1,1-diethyl-3-hydroxybutylene,2,2-dimethyl-3-hydroxybutylene and 2,2-diethyl-3-hydroxybutylene.

Examples of Z¹ and Z² include a hydrogen atom, a fluorine atom, achlorine atom, a bromine atom, an iodine atom, a methyl group, an ethylgroup, a n-propyl group, an i-propyl group, a n-butyl group, an i-butylgroup, a sec-butyl group, a t-butyl group, a hydroxy group, a methoxygroup, an ethoxy group, a n-propoxy group, an i-propoxy group, an-butoxy group, an i-butoxy group, a sec-butoxy group and a t-butoxygroup.

Ar is a pyridyl group or a phenyl group. The phenyl group is substitutedwith OR¹ (wherein R¹ is a hydrogen atom or a C₁ -C₄ alkyl group) andwith A {wherein A is a hydrogen atom, a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, a C₁ -C₄ alkyl group or OR² (wherein R²is a hydrogen atom or a C₁ -C₄ alkyl group)}.

Examples of Ar include pyridyl groups and substituted phenyl groupsrepresented later by Q1-Q33.

However, it should be understood that these specific examples ofrespective substituents by no means limit the present invention.

In the above description, "n", "i", "sec" and "t" and for "normal","iso", "secondary" and "tertiary", respectively.

Among the compounds represented by the general formula (I) of thepresent invention, preferred are:

(1) Compounds represented by the general formula (I) of the presentinvention wherein X is a chlorine atom or a bromine atom.

More preferred are:

(2) Compounds (I) of the present invention as defined in (1), wherein Yis C₁ -C₈ alkylene wherein one carbon atom on the straight chain issubstituted with one OH group, Z¹ is a hydrogen atom, a halogen atom ora OR¹ group (wherein R¹ is a hydrogen atom or a C₁ -C₄ alkyl group), andZ² is a hydrogen atom.

Still more preferred are:

(3) Compounds (I) of the present invention as defined in (2), wherein Yis C₁ -C₄ alkylene wherein one carbon atom on the straight chain issubstituted with one OH group,

(4) Compounds (I) of the present invention as defined in (3), wherein Ais a hydrogen atom or OR² (wherein R² is a hydrogen atom or a C₁ -C₄alkyl group), and

(5) Compounds (I) of the present invention as defined in (4), wherein Z¹is a fluorine atom, a chlorine atom or a bromine atom.

Having from 1 to 6 asymmetric carbon atoms, the compounds of the generalformula (I) of the present invention include optical isomers andstereoisomers.

Hereinafter, typical compounds representing the 3(2H)-pyridazinonederivatives and their salts of the present invention are illustrated inthe following Table I, but the present invention should not be limitedthereto.

In Table I, "n", "i", "sec", "Me", "Et", "Pr", "Bu" and "Ph" stand fornormal, iso, secondary, a methyl group, an ethyl group, a propyl group,a butyl group and a phenyl group, respectively.

Q1-Q33 in Table I are groups represented by the following formulas.##STR3##

    ______________________________________    No.  X     Ar      R    Y           Z.sup.1                                               Z.sup.2    ______________________________________    1    Br    Q1      H    CH.sub.2 CH(OH)                                        4-Cl   H    2    Br    Q4      H    CH.sub.2 CH(OH)                                        4-Cl   H    3    Br    Q2      H    CH.sub.2 CH(OH)                                        4-Cl   H    4    Br    Q3      H    CH.sub.2 CH(OH)                                        4-Cl   H    5    Br    Q5      H    CH.sub.2 CH(OH)                                        4-Br   H    6    Br    Q6      H    CH.sub.2 CH(OH)                                        H      H    7    Br    Q7      H    CH.sub.2 CH(OH)                                        H      H    8    Br    Q8      H    CH.sub.2 CH(OH)                                        H      H    9    Br    Q9      H    CH.sub.2 CH(OH)                                        H      H    10   Br    Q10     H    CH.sub.2 CH(OH)                                        H      H    11   Br    Q11     H    CH.sub.2 CH(OH)                                        H      H    12   Br    Q12     H    CH.sub.2 CH(OH)                                        H      H    13   Br    Q13     H    CH.sub.2 CH(OH)                                        H      H    14   Br    Q14     H    CH.sub.2 CH(OH)                                        H      H    15   Br    Q15     H    CH.sub.2 CH(OH)                                        H      H    16   Br    Q16     H    CH.sub.2 CH(OH)                                        H      H    17   Br    Q17     H    CH.sub.2 CH(OH)                                        H      H    18   Br    Q18     H    CH.sub.2 CH(OH)                                        H      H    19   Br    Q19     H    CH.sub.2 CH(OH)                                        H      H    20   Br    Q20     H    CH.sub.2 CH(OH)                                        H      H    21   Cl    Q1      H    CH.sub.2 CH(OH)                                        H      H    22   Cl    Q1      H    CH.sub.2 CH(OH)                                        H      H    23   Cl    Q1      H    CH.sub.2 CH(OH)                                        3-Me   4-Me    24   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-Et   H    25   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.n Pr                                               H    26   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.i Pr                                               H    27   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.n Bu                                               H    28   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.i Bu                                               H    29   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.sec Bu                                               H    30   Cl    Q1      H    CH.sub.2 CH(OH)                                        4-.sup.t Bu                                               H    31   Br    Q1      H    CH.sub.2 CH(OH)                                        3-OMe  4-OMe    32   Br    Q1      H    CH.sub.2 CH(OH)                                        4-OEt  H    33   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.n Pr                                               H    34   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.i Pr                                               H    35   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.n Bu                                               H    36   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.i Bu                                               H    37   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.sec Bu                                               H    38   Br    Q1      H    CH.sub.2 CH(OH)                                        4-O.sup.i Bu                                               H    39   Br    Q1      H    CH.sub.2 CH(OH)                                        2-O.sup.i Pr                                               4-OMe    40   Br    Q1      H    CH.sub.2 CH(OH)                                        3-Cl   4-Cl    41   Br    Q1      Me   (CH.sub.2).sub.2 CH(OH)                                        H      H    42   Br    Q4      H    (CH.sub.2).sub.3 CH(OH)                                        H      H    43   Br    Q4      H    (CH.sub.2).sub.4 CH(OH)                                        H      H    44   Br    Q4      H    (CH.sub.2).sub.5 CH(OH)                                        H      H    45   Br    Q4      H    CH(OH)CH.sub.2                                        H      H    46   Br    Q4      H    CH(OH)(CH.sub.2).sub.2                                        H      H    47   Br    Q4      H    CH(OH)(CH.sub.2).sub.3                                        H      H    48   Br    Q4      H    CH(OH)(CH.sub.2).sub.4                                        H      H    49   Br    Q4      H    CH(OH)(CH.sub.2).sub.5                                        H      H    50   Br    Q4      H    CH.sub.2 CH(OH)CH.sub.2                                        4-Cl   H    51   Br    Q4      H    (CH.sub.2).sub.2 CH(OH)CH.sub.2                                        4-Cl   H    52   Br    Q4      H    (CH.sub.2).sub.2 CH(OH)(CH.sub.2).sub.2                                        4-Cl   H    53   Br    Q4      H    CH(Me)CH(OH)                                        4-Cl   H    54   Br    Q4      H    CH(OH)C(Me).sub.2                                        4-Cl   H    55   Br    Q1      H    CH.sub.2 CH(OMe)                                        4-Cl   H    56   Br    Q1      H    CH.sub.2 CH(OMe)CH.sub.2                                        4-Cl   H    57   Br    Q4      H    CH(OMe)CH.sub.2                                        4-Cl   H    58   Br    Q4      H    CH.sub.2 CH(OEt)                                        4-Cl   H    59   Br    Q4      H    CH.sub.2 CH(O.sup.n Pr)                                        4-Cl   H    60   Br    Q4      H    CH.sub.2 CH(O.sup.n Bu)                                        4-Cl   H    61   H     Q4      H    CH.sub.2 CH(OH)                                        4-Cl   H    62   Br    Q4      Et   CH.sub.2 CH(OH)                                        4-Cl   H    63   Br    Q4      .sup.n Pr                            CH.sub.2 CH(OH)                                        4-Cl   H    64   Br    Q4      H    CH.sub.2 CMe(OH)CH.sub.2                                        4-Cl   H    65   Br    Q1.HCl  H    CH.sub.2 CH(OH)                                        4-Cl   H    66   Br    Q21     H    CH.sub.2 CH(OH)                                        4-Cl   H    67   Br    Q22     H    CH.sub.2 CH(OH)                                        4-Cl   H    68   Br    Q23     H    CH.sub.2 CH(OH)                                        4-Cl   H    69   Br    Q24     H    CH.sub.2 CH(OH)                                        4-Cl   H    70   Br    Q25     H    CH.sub.2 CH(OH)                                        4-Cl   H    71   Br    Q26     H    CH.sub.2 CH(OH)                                        4-Cl   H    72   Br    Q27     H    CH.sub.2 CH(OH)                                        4-Cl   H    73   Br    Q28     H    CH.sub.2 CH(OH)                                        4-Cl   H    74   Br    Q29     H    CH.sub.2 CH(OH)                                        4-Cl   H    75   Br    Q30     H    CH.sub.2 CH(OH)                                        4-Cl   H    76   H     Q31     H    CH.sub.2 CH(OH)                                        4-Cl   H    77   Br    Q1      H    C(Et).sub.2 CH(OH)                                        4-Cl   H    78   Br    Q1      H    C(.sup.i Pr).sub.2 CH(OH)                                        4-Cl   H    79   Br    Q32     H    CH.sub.2 CH(OH)                                        4-Cl   H    80   Br    Q1      .sup.n Bu                            CH.sub.2 CH(OH)                                        4-Cl   H    81   Br    Q1      H    CH(OH)      4-Cl   H    82   Br    Q1      H    CH.sub.2 CH(OH)                                        OH     H    83   Cl    Q1      H                             ##STR4##   4-Cl   H    84   Cl    Q4      H                             ##STR5##   4-Cl   H    85   Br    Q1      H                             ##STR6##   4-Cl   H    86   Br    Q4      H                             ##STR7##   4-Cl   H    87   Cl    Q1      H                             ##STR8##   4-Cl   H    88   Br    Q4      H                             ##STR9##   4-Cl   H    89   Cl    Q1      H                             ##STR10##  4-Cl   H    90   Br    Q4      H                             ##STR11##  4-Cl   H    91   Br    Q1      H                             ##STR12##  4-Cl   H    92   Br    Q1.HCl  H                             ##STR13##  4-Cl   H    93   Br    Q1.HCl  H                             ##STR14##  4-Cl   H    94   Br    Q1      H    CH(OH)CH.sub.2                                        4-Cl   H    95   Br    Q1      H                             ##STR15##  4-Cl   H    96   Br    Q1      H                             ##STR16##  4-Cl   H    ______________________________________

Methods for preparing the compounds of the present invention areexplained hereinafter.

The 3(2H)-pyridazinone derivatives of the general formula (I) and theirsalts of the present invention can be prepared by the following methodsas illustrated by the reaction formulas (1)-(2). ##STR17## (wherein X¹is a chlorine atom or a bromine atom, and R, X, Y, Z¹, Z² and Ar are thesame as defined above.)

In the preparation method according to the reaction formula (1), a5-halo-3(2H)-pyridazinone compound of the general formula (II) isreacted with an arylmethylamine derivative of the general formula (III)or its salt optionally in the presence of a dehydrohalogenating agent inan inert solvent to produce a compound of the general formula (I).

In this reaction, any inert solvents may be used. For example, an ethertype solvent (such as tetrahydrofuran or 1,4-dioxane), an amide typesolvent (such as formamide, N,N-dimethylformamide orN-methylpyrrolidone), acetonitrile, dimethyl sulfoxide, an alcohol typesolvent (such as methanol, ethanol or propanol), an organic amine typesolvent (such as pyridine, triethylamine, N,N-dimethylaminoethanol ortriethanolamine), water, a hydrocarbon type solvent (such as benzene,toluene, xylene, n-hexane or n-heptane) or a solvent mixture thereof,may be mentioned. Particularly preferred are polar solvents such as anether type solvent, an amide type solvent, acetonitrile, dimethylsulfoxide, an alcohol type solvent, an organic amine type solvent, waterand solvent mixtures thereof.

Any dehydrohalogenating agents may be used so long as they do notadversely affect the reaction and are capable of trapping a hydrogenhalide. As such a dehydrohalogenating agent, an inorganic base such aspotassium carbonate, sodium carbonate, potassium hydrogen carbonate orsodium hydrogen carbonate, or an organic base such asN,N-dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine,N,N-dimethylaminoethanol or pyridine, may be mentioned.

Otherwise, the starting material, an arylmethylamine derivative of thegeneral formula (III), may be used in an excessive amount as thedehydrohalogenating agent.

The reaction temperature may be within a range of from 10° C. to theboiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set.However, the arylmethylamine derivative of the general formula (III) orits salt may be used usually in an amount of from 1 to 10 mols,preferably from 1.2 to 5 mols, relative to one mol of the5-halo-3(2H)-pyridazinone derivative of the general formula (II).

The 5-halo-3(2H)-pyridazinone derivative of the general formula (II) canbe prepared by the conventional process or by application of theconventional organic reaction as described below.

Namely, the 5-halo-3(2H)-pyridazinone derivative of the general formula(II) can be prepared by the methods disclosed in the above-mentionedreferences (c) and (d).

Among the arylmethylamine derivatives of the general formula (III) andtheir salts in the reaction formula (1), those not available ascommercial products can be prepared by the methods disclosed in JapaneseUnexamined Patent Publication No. 267560/1986, European Patent No.186817 and U.S. Pat. No. 5,098,900.

The compound of the formula (I) thus prepared can readily be purified byconventional methods known per se in organic synthesis, such asfractional recrystallization and various silica gel chromatography.##STR18## (wherein X' is an eliminable functional group such as ap-toluenesulfonyloxy group, a methanesulfonyloxy group, a chlorine atom,a bromine atom or an iodine atom, R' is a protecting group, and R, X, Y,Z¹, Z² and Ar are the same as defined above.)

The above reaction formula (2) illustrates a method for preparing acompound of the general formula (I) of the present invention by reactinga 6-hydroxy-5-arylmethylamino derivative of the general formula (IA-a)or (IA-b) with a reactive derivative of the formula (IV). ##STR19## The6-hydroxy-5-arylmethyl derivative of the formula (IA-a) used as thestarting material in the present reaction can be prepared in accordancewith the method disclosed in the above-mentioned reference (c).

The compound (I) can be synthesized by this reaction either via thedirect route as shown in the reaction formula (2)-(i) from the startingmaterial having hydrogen at the 2-positon, or via the route as shown inthe reaction formula (2)-(ii) from the 6-hydroxy-5-arylmethylaminoderivative of the general formula (IA-b) protected at the 2-positionwith R', by converting it into a compound of the general formula (IA-c)and then removing the protecting group R'.

As the protecting group R', tetrahydropyranyl, tetrahydrofuranyl,2-trimethylsilylethoxymethyl (Me₃ SiCH₂ CH₂ OCH₂ --),pivaloyloxymethyl(Me₃ CCO₂ CH₂ --), benzyloxymethyl (PhCH₂ OCH₂ --),hydroxymethyl, methoxymethyl (MeOCH₂ --) or CO₂ R" (wherein R" is alower alkyl group), is preferably used.

The removal of the protecting group R' can easily be conducted by aconventional method for the removal of such protecting groups.

The present reaction can be generally conducted in the presence of aninorganic base such as potassium carbonate, sodium carbonate, lithiumcarbonate, potassium hydrogen carbonate, sodium hydrogen carbonate,lithium hydroxide, etc., or an organic base such as triethylamine,tri-n-propylamine, etc.

As a reaction solvent, a ketone type solvent (acetone, methyl ethylketone, diethyl ketone, etc.), an amide type solvent (formamide,N,N-dimethylformamide, N,N-diethylacetamide, etc.), an alcohol typesolvent (methanol, ethanol, etc.), water and a mixture thereof can besuitably used.

The reaction temperature is usually within a range of from 0° C. to theboiling point of the solvent.

The molar ratio of the starting materials may optionally be determined.However, it is sufficient that the reactive derivative of the generalformula (IV) is used in an amount of from 1 to 5 mols relative to onemol of the compound of the general formula (IA-a) or (IA-b).

The desired compound can be isolated and purified in accordance with themethod as described with respect to the reaction formula (1).

An optically active 3(2H)-pyridazinone derivative of the general formula(I) can be obtained by conventional optical resolution of a racemic3(2H)-pyridazinone derivative (I) as the final product in the reactionformula (1) or (2), or by using an optically active intermediate (II),(IV) or (IA-c) in these reactions.

As the manner of administration of the 3(2H)-pyridazinone derivatives ofthe general formula (I) or their pharmaceutically acceptable salts ofthe present invention, there may be mentioned parenteral administrationin the form of injections (for subcutaneous, intravenous, intramuscularor intraperitoneal injection), ointments, suppositories or aerosols, ororal administration in the form of tablets, capsules, granules, pills,syrups, liquids, emulsions or suspension.

The above pharmacological composition contains a compound of the presentinvention in an amount of from about 0.1 to about 99.5% by weight,preferably from about 0.5 to 95% by weight, based on the total weight ofthe composition.

To the compound of the present invention or to the compositioncontaining the compound of the present invention, otherpharmacologically active compounds may be incorporated.

Further, the composition of the present invention may contain aplurality of compounds of the present invention.

The clinical dose of the compound of the present invention variesdepending upon the age, the body weight, the sensitivity or thecondition, etc. of the patient. However, the effective daily dose isusually from 0.003 to 1.5 g, preferably from 0.01 to 0.6 g, for anadult.

However, if necessary, an amount outside the above range may beemployed.

The compounds of the present invention may be formulated into varioussuitable formulations depending upon the manner of administration, inaccordance with conventional methods commonly employed for thepreparation of pharmaceutical formulations.

Namely, tablets, capsules, granules or pills for oral administration,may be prepared by using an excipient such as sugar, lactose, glucose,starch or mannitol; a binder such as syrups, gum arabic, gelatin,sorbitol, tragacanth, methyl cellulose or polyvinyl pyrrolidone; adisintegrant such as starch, carboxymethyl cellulose or its calciumsalt, crystalline cellulose or polyethylene glycol; a gloss agent suchas talc, magnesium or calcium stearate or silica; or a lubricant such assodium laurate or glycerol.

The injections, syrups, solutions, emulsions, suspensions or aerosols,may be prepared by using a solvent for the active ingredient such aswater, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol, or polyethylene glycol; a surfactant such as a sorbitan fattyacid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene etherof hydrogenated castor oil or lecithin; a suspending agent such as acellulose derivative such as methyl cellulose or sodium carboxymethylcellulose, or a natural rubber such as tragacanth or gum arabic; or apreservative such as a p-hydroxybenzoate ester, benzalkonium chloride ora salt of sorbic acid.

Likewise, the suppositories may be prepared by using e.g. polyethyleneglycol, lanolin or coconut oil.

BEST MODE FOR CARRYING OUT THE INVENTION

Now, the present invention will be described in detail with reference toExamples (including Preparation Examples, Formulation Examples and TestExamples). However, it should be understood that the present inventionis by no means restricted by these specific Examples.

In Preparation Examples, the symbol "MS" indicates "mass spectrum".

PREPARATION EXAMPLES Reference Example 11-(4-chorophenyl)-1,3-propanediol

To a solution of 5.0 g of ethyl-4-chlorobenzoylacetate in 100 ml ofmethylene chloride cooled to -30° C., 77.3 ml of diisopropylaluminiumhydride (1.0 mol/l toluene solution) was added, and the resultingmixture was stirred for 30 minutes and then brought back to roomtemperature over 3 hours, and 4.14 g of methanol and 24.3 g of waterwere added carefully, and the mixture was stirred for another 1.5 hours.The precipitate was filtered off, and the filtrate was concentrated. Theresulting residue was purified by silica gel column chromatography(eluent; n-hexane/ethyl acetate=1/1), to obtain 2.45 g of the titlecompound as a pale yellow oily substance.

Reference Example 2 3-(4-chlorophenyl)-3-hydroxypropyl-1-tosylate

To a liquid mixture of 2.30 g of 1-(4-chlorophenyl)-1,3-propanediol and20 ml of pyridine cooled to -20° C., a liquid mixture of 2.58 g ofp-toluenesulfonyl chloride and 5 ml of pyridine was added. The resultingmixture was stirred at 0° C. for 4 hours, then brought back to roomtemperature and then stirred for another 1 hour. It was cooled again to-20° C., and dilute hydrochloric acid was added until a whiteprecipitate was formed. Then, it was extracted with ethyl acetate. Theextract was washed with a saturated saline solution and dried oversodium sulfate, and the solvent was distilled off. The resulting residuewas purified by silica gel column chromatography (eluent; n-hexane/ethylacetate=3/1) to obtain 3.31 g of the title compound as a pale yellowoily substance.

Reference Example 3 4,5-dibromo-6-3-(4-chloropenyl)-3-hydropropyloxy!-3(2H)pyridazinone

A liquid mixture of 3.86 g of 4,5-dibromo-3,6-dihydroxypyridazine, 3.25g of 3-(4-chorophenyl)-3-hydroxypropyl-1-tosylate, 1.25 g oftriethylamine and 50 ml of N,N-dimethylformamide was stirred at 60° C.for 12 hours. The solvent was distilled off under reduce pressure, thenwater was poured upon the residue, and the residue was dissolved byheating to 100° C. and then allowed to cool. The precipitated crystalswere filtered out and dried under reduced pressure. The crystals thusobtained were recrystallized from methanol-water and washed withmethanol to obtain 1.55 g of the title compound as white crystals havinga melting point of 232°-239° C.

MS (m/e): 436(M⁺), 420, 359, 271, 141 (100%), 133, 77.

Reference Example 4 (2S,3R)-3-(4-chlorophenyl)-2,3-epoxy-1-propanol

To 520 ml of a methylene chloride solution of 10.98 g of titaniumtetraisopropoxide cooled to -70° C., 12 ml of a methylene chloridesolution of 12.07 g of D-(-)-diethyl tartarate was added dropwise, andthe resulting mixture was stirred for 20 minutes. Then, 25 ml of amethylene chloride solution of 12.9 g of p-chlorocinnamyl alcohol wasadded dropwise, and the resulting mixture was stirred for 20 minutes.Then, 42.0 ml of t-butyl hydroperoxide (3.67 mol/l methylene chloridesolution) was added dropwise, and the resulting mixture was stirred at70° C. for 1.5 hours, at -40° C. for 2 hours and at -20° C. for 1.5hours, and then brought to -10° C. over 1 hour and stirred at the sametemperature for 2 hours. After it was cooled again to -20° C., 150 ml ofan aqueous solution of 38.5 g of iron sulfate hexahydrate and 15.4 g ofcitric acid monohydrate was added dropwise over 0.5 hour below 5° C. Themixture was stirred vigorously at 0° C. for 0.5 hour and filteredthrough celite. The filtrate was allowed to separate, and the aqueouslayer was extracted again with methylene chloride. The organic layerswere combined and washed with a saturated sodium hydrogen carbonateaqueous solution, water and a saturated saline solution. After thesolvent was distilled off, the residue was dissolved in diethyl ether,and sodium sulfate and activated carbon were added, and the mixture wasallowed to stand for 0.5 hour. The mixture was filtered through celite,and the ether solution thus obtained was cooled with ice. 172 ml of 1Nsodium hydroxide aqueous solution was added, and then, the resultingmixture was stirred vigorously for 1 hour. After it was allowed toseparate, the organic layer was washed with water (twice) and with asaturated saline solution, treated with activated carbon and filteredthrough celite. After the solvent was distilled off, the residue waspurified by silica gel chromatography (eluent; methanol/chloroform=1/99)and crystallized from cyclohexane to obtain 6.35 g of the title compoundas white crystals of α!_(D) ²⁵ +39.42° (chloroform, c 1.042).

Reference Example 5 (1S)-1-(4-chlorophenyl)-1,3-propanediol

500 ml of a dimethoxyethane solution of 15.0 g of(2S,3R)-3-(4-chlorophenyl)-2,3-epoxy-1-propanol was cooled to -25° C.,and 25.1 ml of a red-Al solution (3.4 mol/l toluene solution) was addeddropwise over 0.5 hour. After stirred at 20° C. for 2 hours, the mixturewas brought to 0° C. over 1 hour, and 300 ml of diethyl ether was addedthereto. While the mixture was kept below 5° C., 100 ml of 2Nhydrochloric acid was added dropwise. After stirring for 15 minutes, themixture was filtered through celite. Then, 100 ml of ethyl acetate wasadded, and the resulting mixture was allowed to separate. The aqueouslayer was extracted again with ethyl acetate. The organic layers werecombined, dried over sodium sulfate and filtered through celite. Thesolvent was distilled off the filtrate, and the resulting residue waspurified by silica gel column chromatography (eluent;methanol/chloroform=5/95). It was crystallized to obtain 14.56 g of thetitle compound as white crystals.

Reference Example 6 (3S)-3-(4-chorophenyl)-3-hydroxypropyl-1-tosylate

To a liquid mixture of 14 g of (1S)-1-(4-chlorophenyl)-1,3-propanediolwith 126 ml of pyridine cooled to -30° C., a liquid mixture of 18.5 g ofp-toluenesulfonyl chloride with 37 ml of pyridine was added dropwise,and the resulting mixture was stirred at room temperature for 3 hours.It was cooled again to -30° C., and after addition of 336 ml of 6Nhydrochloric acid, it was brought to room temperature and extracted withethyl acetate. The extract was washed with a saturated saline solutionand dried over sodium sulfate, and the solvent was distilled off. Theresulting residue was purified by silica gel chromatography (eluent;n-hexane/ethyl acetate=2/1) to obtain 22.8 g of the title compound as apale yellow oily substance.

Reference Example 7 4,5-dibromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxypropyloxy!-3(2H)pyridazinon

A liquid mixture of 27.1 g of 4,5-dibromo-3,6-dihydroxypyridazine, 22.8g of (3S)-3-(4-chlorophenyl)-3-hydroxypropyl-1-tosylate, 8.8 g oftriethylamine and 280 ml of N,N-dimethylformamide was stirred at 70° C.for 5 hours. The solvent was distilled off under reduced pressure, andto the residue, 100 ml of ethyl acetate, 100 ml of a saturated aqueoussodium hydrogen carbonate solution and 100 ml of water were added. Theresulting mixture was stirred at room temperature for 1 hour and thenunder cooling with ice for 1 hour. The precipitated crystals werefiltered out and dried under reduced pressure to obtain 14.65 g of thetitle compound as white crystals.

Example 1 4-bromo-6-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinone(Compound No. 1)

A mixture of 1.50 g of 4,5-dibromo-6-3-(4-chlorophenyl)-3-hydroxylpropyloxy!-3(2H)pyridazinone, 1.48 g of3-picolylamine, 45 ml of methanol and 5 ml of water was refluxed underheating and stirring overnight. The mixture was cooled with ice, and theprecipitated crystals were filtered out and dried under reducedpressure. The resulting crude crystals were recrystallized from methanolto obtain 1.05 g of the title compound as white crystals having amelting point of 212°-214° C.

MS (m/e): 464 (M⁺), 446, 385, 297, 217, 139, 111, 92 (100%), 77.

Example 2 4-bromo-6-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinonehydrochloride (Compound No. 65)

A mixture of 1.0 g of 4-bromo-6-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinone,3 ml of 1N hydrochloric acid, 12 ml of water and 5 ml of ethanol wasstirred at 50° C. for 30 minutes and then cooled with ice. Theprecipitated crystals were filtered out and dried under reduced pressureto obtain 856 mg of the title compound as white crystals having amelting point of 206°-212° C.

MS (m/e): 464 (M⁺ -HCl), 446, 385, 367, 297, 217, 141 (100%), 111, 91,77.

Example 3 4-bromo-6-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3,4-dimethoxybenzylamino)-3(2H)pyridazinone(Compound No. 2)

From 300 mg of 4,5-dibromo-6-3-(4-chlorophenyl)-3-hydroxypropyloxy!-3(2H)pyridazinone, 228 mg of3,4-dimethoxybenzylamine and 69 mg of triethylamine, 246 mg of the titlecompound was prepared in the same manner as in Example 1, as whitecrystals having a melting point of 190°-196° C.

MS (m/e): 523 (M⁺), 446, 277, 196, 151 (100%)

Example 4 4-bromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinone(Compound No. 91)

A mixture of 10.0 g of 4,5-dibromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxypropyloxy!-3(2H)pyridazinone, 9.9g of3-picolylamine, 40 ml of methanol and 4 ml of water was refluxed underheating and stirring overnight and then cooled with ice. Theprecipitated crystals were filtered out and dried under reducedpressure. The resulting crude crystals were recrystallized from a liquidmixture of N,N-dimethylformamide and ethyl acetate to obtain 6.28 g ofthe title compound as white crystals having a melting point of200.5°-201.3° C.

MS (FAB; m/e): 465 (M+1)

Example 5 4-bromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxylpropyloxyl!-5-(3-pyridylylmethylamino)-3(2H)pyridazinonehydrochloride (Compound No. 92)

500 mg of 4-bromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxylpropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinone was dissolved in 5 ml of 10% solution of HCl in ethanol,and the solvent was distilled off. The residue was crystallized frommethanol and diethyl ether. The precipitated crystals were filtered outand dried under reduced pressure to obtain 433 mg of the title compoundas white crystals having a melting point of 176°-181° C.

Example 6 4-bromo-6-(3R)-3-(4-chlorophenyl)-3-hydroxylpropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinonehydrochloride (Compound No. 93)

By using (1R)-l-(4-chlorophenyl)-1,3-propanediol as a starting material,the title compound was synthesized in the same manner as 4-bromo-6-(3S)-3-(4-chlorophenyl)-3-hydroxypropyloxy!-5-(3-pyridylylmethylamino)-3(2H)pyridazinone.

Formulation Examples

    ______________________________________    FORMULATION EXAMPLE 1    Tablets    Compound No. 1           10 g    Lactose                  20 g    Starch                   4 g    Starch for paste         1 g    Magnesium stearate       0.1 g    Calcium carboxymethylcellulose                             7 g    Total                    42.1 g    ______________________________________

The above components were mixed in a usual manner, and formulated intosugar-coated tablets each containing 50 mg of an active ingredient.

    ______________________________________    FORMULATION EXAMPLE 2    Capsules    Compound No. 3         10 g    Lactose                20 g    Crystalline cellulose  10 g    Magnesium stearate     1 g    Total                  41 g    ______________________________________

The above components were mixed in a usual manner, and filled intogelatin capsules to obtain capsules each containing 50 mg of an activeingredient.

Test Example Antiplatelet Aggregation Effect Test Method

Blood was collected from the abdominal aortae of male Wister rats(weight: 200 to 300 g) or male Japanese white rabbits (weight: 1.8 to2.5 kg) into a syringe containing 1/10 volume 3.8% sodium citrate. Theblood thus obtained was centrifuged at 200×g for 7 minutes at roomtemperature to obtain platelet rich plasma (PRP). Furthermore, theresidue was centrifuged at 2000×g for 10 minutes to obtain platelet poorplasma (PPP). The measurement was effected by diluting PRP and PPP to300,000/mm³. PRP and PPP were put in cuvettes, and the measurement rangeof transmittance was adjusted to 0% in the case of PRP and to 100% inthe case of PPP. Thereafter, a test sample drug dissolved in 100%dimethyl sulfoxide (DMSO) was added to PRP (the final concentration ofDMSO: 0.25%). After incubation at 37° C. and 900 rpm for 2 minutes, anaggregating agent was added to measure an aggregation curve. Theantiplatelet aggregation effect of the test sample drug was expressed bya concentration, IC₅₀ (μM), at which the aggregation of control samplewas 50% inhibited. The aggregating agents ADP and collagen were used atminimum concentrations (ADP: 5 to 10 μM: collagen : 2.5 to 10 μg/ml)which caused maximum aggregation. The measurement of plateletaggregation was carried out by using NBS HEMA TRACER 601.

Test Results

Tables II and III show antiplatelet aggregation effects of testcompounds evaluated as IC₅₀ values (μM).

As a comparative compound, the following compound disclosed in reference(d) was used. ##STR20##

                  TABLE II    ______________________________________    Test Compound   Rat PRP  ;IC.sub.50 (μM)    No.             ADP      Collagen    ______________________________________    1               0.23     0.099    2               0.072    0.19    65              0.21     0.22    ______________________________________

                  TABLE III    ______________________________________    Test Compound     Rabbit PRP                                ;IC.sub.50 (μM)    No.               ADP       Collagen    ______________________________________     1                0.050     0.010     2                0.041     0.02    65                0.053     0.019    93                0.047     0.0097    Comparative Compound                      0.081     0.017    Cilostazol        15        2.4    ______________________________________

The results demonstrate that the compounds of the present invention haveantiplatelet aggregation effects coparable to or higher than that of thecomparative compound.

Test Example 2 Vasodilation Effect Test Method

By using a rabbit thoracic aorta ring specimen, the relaxation effect ofa test sample drug on contraction by phenylephrine (10⁻⁵ M) wasevaluated. A test sample drug was administered cumulatively from aconcentration of 3×10⁻⁹ M, after the contraction became stable. Theresults were expressed on the basis that the relaxation effect ofpapaverine hydrochloride (10⁻⁴ M) was 100%.

Test Results

Table IV shows vasodilation effects of test compounds evaluated as EC₅₀values (μM). The comparative compound was the same as in Test Example 1.

                  TABLE IV    ______________________________________    Test Compound    No.               EC.sub.50 (μM)    ______________________________________    1                 1.3    Comparative Compound                      0.4    ______________________________________

These results demonstrate that the compound of the present invention hasa still weaker vasodilation effect than the comparative compound and, asan antiplatelet agent, has weak side effect.

INDUSTRIAL APPLICABILITY

As evident from the above results, it is clear that the compound of thepresent invention show an extensive and broad spectrum in inhibition ofplatelet aggregation and can be an excellent antiplatelet agent whichacts very selectively and is useful in respect of efficacy and sideeffects. Thus, the compound of the present invention can be usefulprophylactic and therapeutic drugs for various thrombotic diseases.

We claim:
 1. A 3(2H)-pyridazinone compound of the formula (I): ##STR21##wherein R is a hydrogen atom or a C₁ -C₄ alkyl group, X is a hydrogenatom, a chlorine atom or a bromine atom,Ar is a pyridyl group, Y is C₁-C₈ alkylene wherein one carbon atom on the straight chain issubstituted with one OR¹ group, wherein R¹ is a hydrogen atom or a C₁-C₄ alkyl group, and Z¹ and Z² are independently a hydrogen atom, ahalogen atom, a C₁ -C₄ alkyl group or a OR¹ group, wherein R¹ is thesame as defined above, or a pharmaceutically acceptable salt thereof. 2.The 3(2H)-pyridazinone compound according to claim 1, wherein X is achlorine atom or a bromine atom, or a pharmaceutically acceptable saltthereof.
 3. The 3(2H)-pyridazinone compound according to claim 2,wherein Y is C₁ -C₈ alkylene wherein one carbon atom on the straightchain is substituted with one OH group,Z¹ is a hydrogen atom, a halogenatom or a OR¹ group, wherein R¹ is a hydrogen atom or a C₁ -C₄ alkylgroup, and Z² is a hydrogen atom, or a pharmaceutically acceptable saltthereof.
 4. The 3(2H)-pyridazinone compound according to claim 3,wherein Y is C₁ -C₄ alkylene wherein one carbon atom on the straightchain is substituted with one OH group, or a pharmaceutically acceptablesalt thereof.
 5. The 3(2H)-pyridazinone compound according to claim 1,wherein Z¹ is a fluorine atom, a chlorine atom or a bromine atom, or apharmaceutically acceptable salt thereof.
 6. A method for preparing the3(2H)-pyridazinone compound according to claim 1 or a salt thereof,which comprises reacting a 5-halo-3(2H)-pyridazinone compound of theformula (II): ##STR22## wherein R is a hydrogen atom or a C₁ -C₄ alkylgroup, X is a hydrogen atom, a chlorine atom or a bromine atom,X¹ is achlorine atom or a bromine atom, Y is C₁ -C₈ alkylene wherein one carbonatom on the straight chain is substituted with one OR¹ group, wherein R¹is a hydrogen atom or a C₁ -C₄ alkyl group, and Z¹ and Z² areindependently a hydrogen atom, a halogen atom, a C₁ -C₄ alkyl group or aOR¹ group, wherein R¹ is the same as defined above, with anarylmethylamine derivative of the formula (III):

    H.sub.2 NCH.sub.2 --Ar                                     (III)

wherein Ar is a pyridyl group or a salt thereof, optionally in thepresence of a deacidifier.
 7. An antiplatelet agent containing aneffective amount of the 3(2H)-pyridazinone or a compoundpharmaceutically acceptable salt thereof as defined in claim 1 as anactive ingredient.
 8. A method for inhibiting platelet aggregation in asubject in need thereof, comprising administering to said subject anantiplatelet effective amount of the 3(2H)-pyridazinone or apharmaceutically acceptable salt thereof as defined in claim 1.